Transplantation of human neural stem cells protect against ischemia in a preventive mode via hypoxia-inducible factor-1α stabilization in the host brain
- 作者：Kon Chu ; Keun-Hwa Jung ; Se-Jeong Kim ; Soon-Tae Lee ; Juhyun Kim ; Hee-Kwon Park ; Eun-Cheol Song ; Seung U. Kim ; Manho Kim ; Sang Kun Lee ; Jae-Kyu Roh
- 关键词：Deferoxamine ; Hypoxia-inducible factor-1 ; Ischemic prevention ; Neural stem cell ; Transplantation
- 刊名：Brain Research
- 出版年：2008
- 期刊代码：8_00068993
- 类别：neu
- 出版时间：1 May 2008
- 卷：1207
- 期：Complete
- 页码：182-192
- 文件大小：1060 K
摘要
Hypoxia-inducible factor-1 (HIF-1) plays important roles in the prevention of cerebral ischemia. Deferoxamine (DFX), an iron chelator stabilizes the HIF-1
and activates target genes involved in compensation for ischemia. In this study, we are to investigate whether HIF-1 can be stabilized in human neural stem cells (NSCs) by DFX, and pre-transplantation of NSCs with HIF-1 stabilization can induce prolonged ischemic tolerance. In the DFX-treated NSCs, the HIF-1 protein expression was increased about 100-fold time-dependently, and subsequent transcriptional activation (VEGF, BDNF and CXCR4) was also observed. To test an ability to induce ischemic prevention in vivo, DFX-treated NSCs or naïve NSCs were transplanted in the striatum of adult rats. Seven days following the transplantation, focal cerebral ischemia was done. Infarct volumes were reduced in both NSCs-transplanted groups, compared with ischemia-only, but more reduced in DFX-treated NSCs group. The protective effects of NSCs were ablated when HIF-1 was silenced. HIF-1 protein levels were increased in both NSCs-transplanted groups, but more increased in DFX-treated NSCs group. RT-PCR analysis manifested a downregulation of mRNA expression of TNF-, IL-6 and MMP-9 in both NSCs groups, but further decrease in DFX-treated NSCs group. These findings provide evidence that HIF-1 stabilization in human NSCs can be achieved effectively by DFX, and HIF-1-stabilized NSCs protect against ischemia in a preventive mode.
and activates target genes involved in compensation for ischemia. In this study, we are to investigate whether HIF-1 can be stabilized in human neural stem cells (NSCs) by DFX, and pre-transplantation of NSCs with HIF-1 stabilization can induce prolonged ischemic tolerance. In the DFX-treated NSCs, the HIF-1 protein expression was increased about 100-fold time-dependently, and subsequent transcriptional activation (VEGF, BDNF and CXCR4) was also observed. To test an ability to induce ischemic prevention in vivo, DFX-treated NSCs or naïve NSCs were transplanted in the striatum of adult rats. Seven days following the transplantation, focal cerebral ischemia was done. Infarct volumes were reduced in both NSCs-transplanted groups, compared with ischemia-only, but more reduced in DFX-treated NSCs group. The protective effects of NSCs were ablated when HIF-1 was silenced. HIF-1 protein levels were increased in both NSCs-transplanted groups, but more increased in DFX-treated NSCs group. RT-PCR analysis manifested a downregulation of mRNA expression of TNF-, IL-6 and MMP-9 in both NSCs groups, but further decrease in DFX-treated NSCs group. These findings provide evidence that HIF-1 stabilization in human NSCs can be achieved effectively by DFX, and HIF-1-stabilized NSCs protect against ischemia in a preventive mode.